Invasion and proliferation in neoplasia requires the cooperation of tumor, cell and endothelial compartments. Glycogen synthase kinase-3 (GSK-3) is increasingly recognized as a major contributor to signaling pathways that modulate invasion and proliferation. Here we show that GSK-3 inhibitors of the indirubin family reduce invasion of glioma cells and glioma-initiating cell-enriched neurospheres both in vitro and in vivo, and we demonstrate that •-catenin signaling plays an important role in mediating these effects. Indirubins improved survival in glioma-bearing mice where a substantial decrease in blood vessel density was seen in treated animals. Additionally, indirubins blocked migration of endothelial cells, suggesting that anti-invasive glioma therapy with GSK-3 inhibitors in vivo not only inhibits invasion of tumor cells, but blocks migration of endothelial cells, which is also required for tumor angiogenesis. Overall, our findings suggest that indirubin inhibition of GSK-3 offers a novel treatment paradigm to target two of the most important interacting cellular compartments in heterotypic models of cancer.

PMID: 21697283 [PubMed - as supplied by publisher] Source: National Library of Medicine.